Precision-cut liver slices as an alternative method for long-term hepatotoxicity studies
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LETTER TO THE EDITOR, NEWS AND VIEWS
Precision‑cut liver slices as an alternative method for long‑term hepatotoxicity studies Amnah Othman1 · Sabrina Ehnert1 · Anne Dropmann2,3 · Marc Ruoß1 · Andreas K. Nüssler1 · Seddik Hammad2,4 Received: 14 July 2020 / Accepted: 15 July 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Nowadays, there are several attempts to establish hepatocyte (HC)-based in vitro systems as alternatives for animal experiments. It has been reported that HC recapitulate some in vivo features under certain culture conditions (Messner et al. 2013). However, HC lose their polarization and metabolic activity rapidly in culture (Godoy et al. 2013, 2016; Hammad 2013). Therefore, screening for an alternative method maintaining HC functions i.e. metabolic activity and their natural 3D microenvironment is currently needed for long-term hepatotoxicity studies (Hammad et al. 2015; Vinken 2020; Ruoß et al. 2020). To date, the only known alternative method, without separating cells and keeping the natural cellular environment with a full metabolic program, are precision-cut liver slices (PCLS). HC in PCLS retain their apical and sinusoidal membranes and maintain cell-cells/ECM contacts. Therefore, PCLS allow an efficient use of rodent (Reduction; Refinement) and human (Replacement) livers for several studies i.e. hepatotoxicity. Historically, PCLS have firstly been generated by Krumdieck and co-workers in 1980 (Krumdieck et al. 1980). Standardization of PCLS culturing protocols are key to maintain viability at least for 96 h in culture when incubated under a 95% O2/5% CO2 atmosphere (de Graaf et al. 2010). Recently, * Seddik Hammad [email protected]‑heidelberg.de 1
Department of Traumatology, Siegfried Weller Institute, BG Clinic, Eberhard Karls University Tübingen, Tübingen, Germany
2
Molecular Hepatology Section, Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
3
Hepatology and Bioinformatic Section, Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
4
Department of Forensic Medicine and Veterinary Toxicology, Faculty of Veterinary Medicine, South Valley University, Qena, Egypt
Bigaeva et al (2019) suggest the applicability of PCLS as an ex vivo fibrosis model. In their study, PCLS are harvested from healthy and diseased mouse and human livers. Beside the culturing impacts, PCLS show species-, organ- and disease stage-specific differences by transcriptomic analyses. Palma and co-workers have recently applied a perfusion step prior slicing to further maintain viability and functionality of human (Replacement)-derived PCLS (Palma et al. 2019) to improve life-span of the slices. Moreover, human (Replacement) and rat (Reduction; Refinement) PCLS are generated from healthy (Pearen et al. 2020) or fibrotic livers and cultured in a bioreactor (Paish et al. 2019). Also, Paish et al. convincingly describe a no
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